1. Technical Field
The present invention refers to new compositions comprising at least one bactericidal antibiotic from the group of macrolides and a non-steroidal anti-inflammatory with selective inhibiting activity for cyclooxygenase 2 (COX-2).
The present invention also refers to dosage forms of said compositions, consisting of tablets and similar, provided with double coating layer.
Among the bacterial affections for which the compositions of the present invention are effective, we highlight respiratory affections caused by Bordetella spp, Chlamydia spp, Haemophilus spp, Pasteurella spp, Shigella spp, Streptococcus spp, Escherichia coli, Staphylococcus aureus; affections of the skin and attachments caused by Corynebacterium spp, Staphylococcus aureus, Staphylococcus intermedius, Escherichia coli, Streptococcus spp, Pausterella multocida; genitourinary affections caused by Streptococcus spp, Escherichia coli, Staphylococcus aureus); digestive affections such as diarrheas caused by Escherichia coli; oral affections such as gingivitis and periodontitis, as well as septic arthritis, osteomyelitis and discoespondilitis caused by Escherichia coli. 
Compositions of the present invention are also indicated for use in post-surgery arthroplasties, bone surgeries, orthodontic surgeries, periodontal disease treatments or prophylaxis and general traumas in pet animals, particularly dogs and cats.
Among inflammatory affections for which the compositions of the present invention are effective, we highlight those disturbing the motor system, such as joints, bones and muscles, as well as other joints such as the spinal column. In this sense, the compositions of the present invention provide wide spectrum antibiotic therapy, combating the cause of infections, while treating inflammation and its effects.
Therefore, the present invention also contemplates a method to treat pet animals.
2. Related Art
Azithromycin is the first pharmaceutical product of the class of azalides. Azalides are derived from erythromycin and their mechanisms of action are similar. Azithromycin, or 9-deoxo-9a-aza-9a-methyl-9a-homoerithromycin A, has the molecular formula C38H72N2O12 and presents the following chemical structure:

Technical and scientific literature about this pharmaceutical product is wide and discloses that azithromycin presents better oral absorption, is better tolerated, has much longer half-life, especially in tissues, and wide spectrum of activity. It is a modern antibiotic presenting, besides wide spectrum of action, pharmacokinetic characteristics allowing high intracellular concentrations and long permanence in tissues, thus providing therapeutic results with shorter treatment period. This antibiotic is active against Gram-positive aerobic bacteriae, staphylococcus and streptococcus, as well as anaerobic bacteriae. It has good activity against various intracellular microorganisms, including Chlamydia and Toxoplasma, being also active against mycobacteriae and Mycoplasma. Azithromycin is extraordinarily able to concentrate in tissues, particularly leucocytes, macrophages and fibroblasts. Concentration in tissues may reach up to 100 times the value of serum concentrations and concentrations in leucocytes may be of at least 200 to 300 times concentrations in serum. In cats, half life in serum is mentioned as being 35 hours, half life in tissues varies between 13 and 72 hours and Vd is 23 I/kg. In dogs, azithromycin also presents quick absorption and persistent concentrations in tissues. Vd is 12 l/kg, while half life in plasma and tissues is 29 to 90 hours, respectively. Oral absorption is high, with bioavailability values of about 58% in cats and about 97% in dogs. Therefore, it is particularly interesting that the intracellular reservoir of azithromycin may apparently produce efficient concentrations of the pharmaceutical product in gut fluids, even after plasma concentrations have fallen below detectable levels. Intracellular stocks of Azithromycin in leucocytes may also serve as a form to release the pharmaceutical product to infected tissues, especially in premature abscesses, since leucocytes are attracted to those places by chemotaxis. Slow release of Azithromycin by leucocytes distinguishes Azithromycin from other macrolides and fluoroquinolones which, despite reaching high concentration in leucocytes, are quickly released from cells in environments which are free from the pharmaceutical product.
Concerning anti-inflammatory products, the large majority available for veterinary use so far comprises active principles not selectively active for cyclooxygenase 2 (COX-2) and, despite having satisfactory analgesic and anti-inflammatory action, cause side effects in a large number of treated animals, mainly in cases requiring longer therapy. In these cases, due to the appearance of side effects, therapy should be interrupted before the resolution of the clinic profile. Among them, we can mention meloxicam, or 4-hydroxy-2-methyl-N-(5-methyl-2-thiazolyl)-2H-1,2-benzotiazine-3-carboxamide-1,1-dioxide, a compound with the molecular formula C14H13N3O4S2 and structural formula:

Meloxicam is a powerful inhibitor of tromboxanes (TXs) and prostaglandins (PGs), with excellent antipyretic and analgesic properties, being used to treat affections of the muscles and skeleton, as well as pre-surgically. In the wide technical and scientific literature about such anti-inflammatory product, we found references considering it as a preferential COX-2 inhibitor. The main mechanism of action of meloxicam is to regulate the synthesis of prostaglandins, by inhibition of the enzyme system of cyclooxygenase (COX). Such action is responsible for the anti-inflammatory, anti-exudative, analgesic and antipyretic effects. Besides said effects, meloxicam also inhibits the infiltration of leucocytes into inflamed tissue and avoids bone and cartilage destruction as occurs in degenerative inflammation processes. In long term studies undertaken with rats and mice, meloxicam has shown chondroneutral action, being therefore especially indicated for long term treatments of osteoarthritis.
It is also known that the incidence of complications, such as hemorrhage and gastric perforation, is not equal for all non-steroidal anti-inflammatory products. There have been attempts to explain such differences based on “partial selectivity” for COX-2 inhibition. The existence of at least two isoforms of cyclooxygenase constituted by cyclooxygenase 1 (COX-1) and by COX-2 has recently been discovered. Isoenzyme COX-1 is responsible for the production of prostaglandins in the gastrointestinal route, promoting the protection of stomach mucosa against the action of gastric juice, and in kidneys, where they regulate its blood flow. The isoenzyme COX-2 has the main purpose to respond against inflammatory processes.
COX-2 selective inhibition causes an important reduction in the inflammatory process, without the consequences related to COX-1 physiological regulation feature. The clinical repercussion of said phenomenon is the inhibition of pain and inflammation with less toxicity in places where prostaglandins have an important action, such as in the stomach and kidneys. COX-2 is an inducible form, being formed from stimuli, such as the presence of endotoxins and inflammatory stimuli releasing cytokines which, on the other hand, induce the synthesis of COX-2 by cells such as macrophages, resulting in the release of inflammatory PGs, i.e. COX-2 is induced by the inflammatory reaction itself. The release of PGs together with proteases and other inflammatory mediators, such as oxygen-free radicals, result in inflammation.
Therefore, it has been hypothesized that COX-2 is the main responsible for the synthesis of prostanoid mediators of pain, inflammation and fever.
COX-2 route may be interrupted at various levels by antagonists or antibodies for cytokines and mitogens inhibiting COX-2 induction, such as glucocorticoids or effective COX-2 inhibitors. Therefore, the higher or lower probability of an AINE causing adverse effects is conditioned to its ability to selectively inhibit just COX-2. This knowledge made research turn to the discovery of drugs affecting COX-1 at a lower scale, thus having better safety margin and fewer side effects, keeping, on the other hand, enough actuation in COX-2 to provide a good analgesic, antipyretic and anti-inflammatory effect.
Studies made with meloxicam have shown that it acts selectively or preferentially at COX-2, promoting about 80 to 90% inhibition of said enzyme and about 20% only for COX-1 inhibition. This is why this is the elected drug for anti-inflammatory treatments, presenting excellent analgesic, antipyretic, anti-inflammatory and anti-exudative action with minimum side effects. Meloxicam is widely used for veterinary medicine as a general anti-inflammatory and particularly for pathological processes affecting bones, muscles and cartilages, where it acts by inhibiting the infiltration of defense cells into inflamed tissues. Experiments have proved the excellent actuation of that drug in muscle and skeleton affections which even need long anti-inflammatory therapy, being most indicated selective COX-2 inhibitors, such as meloxicam, due to the better safety margin, since dogs and cats are particularly affected by the side effects of anti-inflammatory therapies.
Pharmacokinetic studies made by giving meloxicam to rats, mice, dogs and guinea pig by oral and intravenous routes have shown that said compound has been well absorbed after oral administration in mice and dogs, with bioavailability of at least 70% in mice and 100% in dogs. Oral absorption is not changed by the simultaneous ingestion of food. Half life of the drug is between six and eight hours.
Various other experimental studies were carried out, both in Brazil and abroad, to prove the efficacy and tolerance of meloxicam in dogs and cats. One of them, conducted in Germany, evaluated the efficacy and tolerance of a treatment with meloxicam where animals have been submitted to twice and three times the recommended dosage of the active principle, administered by the subcutaneous parenteral route. No side effects or any hematological or chemical blood change have been observed. In a controlled field study, the clinical efficacy of meloxicam in dogs with acute motor disorders, when submitted to a one-week treatment with the drug, has been proved. During that week, side effect levels lower than 2% were noticed. The clinical efficacy was considered excellent or good in 87.9% and 95.3% of cases, respectively.
In another assay, conducted by the Octávio Bastos Veterinary Medicine Faculty—São João da Boa Vista, Sao Paulo, Brazil, meloxicam was administered to a group of dogs for twenty-one consecutive days, not causing any gastrointestinal dysfunction, change in mucosa color or animal appetite, showing higher tolerance to said drug for long treatments, in comparison with other anti-inflammatory products commonly used for dogs.
In another assay, conducted in Florida, United States, the clinical efficacy of meloxicam against ketoprofen in cats with painful motor disorders was evaluated. Sixty-nine dogs with acute or chronic motor disorders were recruited. Animals were treated for five consecutive days. Results have shown significant improvements in behavior, food ingestion and gain of weight and a significant reduction in claudicating, pain and inflammation. No differences between both treatment groups were noticed concerning measured parameters. Meloxicam was considered an effective analgesic product, well tolerated in cats with acute or chronic muscle and skeleton disorders in treatments of up to five consecutive days, also presenting a better palatability and easy administration for those animals.
In Madrid, an assay was carried out to evaluate the efficacy of meloxicam as an analgesic intended to control chronic pain, as well as its analgesic action when administered before surgical procedures. Obtained results have shown that meloxicam as administered before surgery presents large efficacy in surgical analgesia, significantly acting with opioids, reducing the required quantity of halothane to effect anesthesia and also providing an excellent rate of post-surgical analgesia due to its long period of action.
Furthermore, another assay conducted in Barcelona evaluated the efficacy and tolerance of meloxicam in dogs with change in the motor system. Results led to the conclusion that meloxicam is a powerful non-steroid anti-inflammatory with excellent clinical response in acute and chronic affections of the motor system. Tolerance against meloxicam was found in about 86.5% of cases. Secondary effects, as noticed during the three weeks of treatment, had less importance, since, except in one case, it was not necessary to suspend the medication.
The use of drugs Azithromycin and meloxicam is widely known in the therapy of dogs and cats. Azithromycin is a wide spectrum antibiotic. Meloxicam is a COX-2 selective non-steroidal anti-inflammatory product, thus reducing side effects, such as gastritis and reduction in immunity, being indicated for the treatment of general inflammatory processes. Frequently, meloxicam is prescribed for administration with antibiotics to minimize the inflammatory process generated in case of infections.
Currently, Azithromycin and meloxicam are administered separately; being the dog or cat forced to ingest at least one tablet of each substance, what makes the administration become difficult and may also cause worse stomach irritation. Furthermore, when two pharmaceutical products are administered in separate formulations, each substance will be absorbed at a time and the peaks of each pharmaceutical product will occur in different times. Thus, the effect of each pharmaceutical product is obtained in different times in the animal, and there is no simultaneous and complementary effect to the use of antibiotics and an anti-inflammatory product.
For the above reasons, Azithromycin and meloxicam have never been administered in one single dosage, for simultaneous treatments of bacterial and inflammatory affections.